Transdermal administration of (r)-3,3-diphenylpropylamin-monoesters

ABSTRACT

The invention relates to a device for transdermally administering a compound of formula (I), wherein A represents hydrogen or deuterium, R represents a group selected among C 1-4 alkyl, C 3-10 cycloalkyl, or phenyl, each of which can be substituted by C 1-3  alkoxy, fluoride, chlorine, bromine, iodine, nitro, amino, hydroxy, oxo, mercapto, or deuterium, the C atom marked by * (asterisk) being provided in the R configuration. The invention is characterized in that the compound of general formula (I) is provided in a polymer matrix and is released at a dose of 0.5 to 20 mg per day through human skin. The invention further relates to the use of said compounds of formula (I) for producing transdermal medicaments.

The invention concerns a medicine for the transdermal delivery of(R)-3,3-diphenylpropylamine-monoesters as well as their application forthe manufacture of a medicine for transdermal delivery.

The proportion of seniors within the total population has gone upsignificantly in the past 50 years. Bladder dysfunctions belong to themost common geriatric diseases in this group. Therefore, ever greaterand more specific significance is being attached to the development of amost effective and gentle treatment of bladder complaints.

In the case of urge incontinence the dysfunction lies in a malfunctionof the bladder muscle. Frequently the cause is a stimulation or moreprecisely a hyperactivity of the muscarinic receptors. For this reasonuse of the antimuscarinic active ingredients Tolterodin and Oxybutyninis preferred for the treatment of the hyperactive bladder and theassociated symptoms such as increased urinary urgency, abnormallyfrequent micturation or nocturia.

However, Oxybutynin is an effective antimuscarinic active ingredientthat has serious side effects. Notably the pronounced dryness of themouth is felt by many patients to be extremely unpleasant.

By comparison with Oxybutynin Tolterodin appears to exhibit lower ratesof muscarinic side effects. In an organism Tolterodin is predominantlydealkylated into active main metabolites2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol bythe cytochrome P450-isoenzyme 2D6 as well as—slowly—into inactivemetabolites by the cytochrome P 450 isoenzyme 3A4.

Since Tolterodin is metabolized exclusively by the P450-isoenzyme, thereis the potential danger of interactions with the breakdown of otheractive ingredients, for example, with Warfarin (Colucci, Annals ofPharmacotherapy 33, 1999, 1173), antimycotics such as Ketoconazol(Brynne, Br J Clin Pharmacol 48, 1999, 564) macrolide antibiotics orprotease inhibitors. This danger is present particularly in the case ofthe so-called slow metabolizers, which have a lack of 2D6, metabolizeTolterodin exclusively through 3A4 and exhibit a distinctly increasedTolterodin concentration in plasma.

WO 99/58 478 describes new derivates of 3,3-diphenylpropylamines asactive muscarinic ingredients. The disclosed3,3-diphenylpropylamine-derivates are prodrugs from2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol andare hydrolyzed by esterases upon entering through biological membranesas well as in plasma. For this reason the 2D6-dependent degradationdevice does not apply.

In contradistinction to Tolterodin such 3,3-diphenylpropylaminederivates, for example,2-[3-(1,1-Diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenylisobutyrate (INN: fesoterodine), therefore do not show a tendencytowards accumulation even in the case of slow metabolizers, they do notinterfere with P450 inductors/inhibitors and they possess anadvantageous safety profile with regard to potential interactions ofactive ingredients and accumulation of active ingredients.

Therefore, the need arose to make the advantages of the3,3-diphenylpropylamine derivate described in WO 99/58478, particularlythe advantages of the fesoterodine, available to the collective ofpatients. The metabolism method of Tolterodin and the disadvantages ofOxybutynin (dry mouth) alone make clear the medical need for a medicinethat does not exhibit the disadvantages of both of the previously namedsubstances.

3,3-diphenylpropylamine monoesters may be present as stabile crystallinesalts. fesoterodine-hydrogen fumarate is an example preferred for thispurpose. Salts of this sort are described in WO 01/35957 and areparticularly suited for oral or parenteral treatment of the hyperactivebladder.

Even though oral administration of these compounds represents anappropriate form of presentation for most patients, there is a need foran alternative form of administration. This need results not least atthe old ages of the patients affected by dysfunctions of bladdermotility, in which cases an array of reasons are able to speak againstthe oral administration of the drugs.

There is frequently a multimorbidity within this collective of patients,whereby as a general rule the patients are taking several differentmedications. Avoidance of passage through the intestine and the firstliver passages and consequently a non-oral form of administration arefrequently desirable to prevent interactions with the resorption ofother drugs and/or not to burden the gastrointestinal tract as well asthe liver with additional drugs.

In addition, a number of older patients have problems with swallowingthe solid forms of drugs, while other geriatric patients exhibitimpaired gastrointestinal absorption, for example, as a result of acuteor chronic gastrointestinal diseases or the taking of anti-infectives.

Ultimately a more constant plasma concentration of the active substancecan be achieved using a form of administration that avoids thefirst-pass effect of the first liver passage and that also exhibits aretarding effect, which in general simultaneously leads to a lowering ofthe danger of undesired side effects, dryness of the mouth inparticular, with unaltered or even improved clinical effectivity.

The transdermal administration of a 3,3-diphenylpropylamine-monoesterand in particular of fesoterodine is an attractive option because, forinstance, it avoids the peak concentrations in the plasma associatedwith oral administration and the danger of muscarinic side effectsassociated with it, notably dryness of the mouth.

If there is success in transporting the most even dose possible of theactive agent into the circulatory system over a longer period of time,the total daily dose and with it the effectiveness of the activeingredient could be raised and the occurrence of undesired side effectslowered at the same time.

It was therefore an objective of this invention to provide a device or amedicine respectively for the transdermal delivery of a compound of thegeneral Formula I which satisfies the following conditions:

-   -   1. The device should be able to administer a therapeutically        effective daily dose of a 3,3-diphenylpropylamine-monoester        transdermally.    -   2. The active ingredient should be administered in a        therapeutically effective amount through the skin over a longer        period of time, meaning over at least 24 hours, preferably over        48 or 72 hours following the one time application of the        medicine.    -   3. The active ingredient should be taken in through the skin at        the most constant rate possible so that a nearing constant        plasma level is sustained over the scheduled duration of        application.    -   4. The surface of the skin, which is in contact with the device        (e.g. the patch) should preferably be a maximum size of 50 cm².    -   5. A skin penetration enhancer should be dispensed with, if        possible.    -   6. The device should be constructed as simply as possible and be        producible as cost-effectively as possible.

The suitability of a transdermal medicine for the controlledadministration of active ingredients, preferably for several days, isnow being influenced by a number of parameters and requirements, forexample,

-   -   The type of transdermal preparation (ointment, gel, patch,        spray),    -   Control of the release of the active ingredient (passive        diffusion, iontophoresis, ultrasound, electroporation)    -   Concentration of the active ingredient, loading and saturation        of the form of application,    -   The cutaneous permeability for the active ingredient under        occlusive conditions, for example, following application of a        patch,    -   The type of retarding principle that is being used to ensure a        continual steady-state flux over one or several days,    -   The manufacturing procedure of the form of administration,    -   the required daily dose of the active ingredient,    -   The use of the active ingredient in optimum form (base, salt,        state of aggregation, optical configuration).

A medicine for controlled transdermal delivery is consequently a highlycomplex system, in which a multitude of factors often have anunforeseeable influence on the properties of the formulation of theactive ingredient and the penetration of the skin.

So despite many years of efforts by the pharmaceutical industry, thereare still no forms of transdermal administration of an active muscarinicingredient, such as Oxybutynin or Tolterodin, for example, obtainable onthe market today.

Also, the transdermal delivery of the Tolterodin primary metabolites2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol isstill not yet clinically possible due to its very low rate ofpenetration through the human skin (see Table 1).

There is a suggestion implicated in WO 99/58478 that in principle3,3,-diphenylpropylamine-monoesters can permeate the skin if a solutionof a substance is subjected to a test in compliance with Thiemessen(Acta Pharm Technol 34, 1999, 99). However, WO 99/58478 does not containany teaching on how a device for the transdermal administration has tobe arranged in order to achieve a most constant transdermal flux of the3,3-diphenylpropylamine monoester active ingredient on patients over alonger period of time.

Moreover, due to low flux rates these transdermal forms of drugs, whichwere manufactured using the known high purity salts from3,3-diphenylpropylamine monoesters from WO 01/35957 are provingthemselves in costly series of measurements to be therapeuticallyunsuitable (Table 1).

It was a surprise now to discover, however, that a compound of thegeneral Formula I

in which A means hydrogen or deuterium, R stands for a group C₁₋₆-alkyl,C₃₋₆-cycloalkyl or phenyl which may each be substituted with fluorine,chlorine, bromine, iodine, hydroxyl, oxo or deuterium and where theC-atom marked with a star “*” is present in the (R)-configuration, canbe transported at a steady flux rate through the human skin during atimeframe of at least 24 hours in an amount of 0.5-20 mg sufficient fortherapeutic treatment of the overactive bladder, if the combination ofthe general Formula I is introduced into a transdermal device in asufficient quantity as a free base in a polymer layer, preferably aself-adhesive polymer layer (adhesive matrix).

Using such a simply constructed, flat shaped device with a surface of amaximum around 50 cm² it is surprisingly possible, to make theclinically relevant dosing spectrum of the combinations of the generalFormula I transdermally available.

One object of the invention is therefore a device for the transdermaldelivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration,characterized by the fact that the combination of the general Formula Iis present in a polymer layer, preferably in a self-adhesive polymerlayer (adhesive matrix), dissolved or dispersed and is released throughthe human skin in a flux rate of 0.5-20 mg per day.

More advantageously the active ingredient is introduced into the polymerlayer, for example, to the adhesive matrix in the form of the free base.

In the sense of the invention it is understood by the expression “freebase” that less than 20 percent by weight, preferably less than 10%, 5%or 3%, especially preferred less than 1% of the compound of the generalFormula I is present in the salt form.

If the high purity salts from 3,3-diphenylpropylamine derivates knownfrom WO 01/35957, for example, the fumarate salt from fesoterodine, areintroduced into the polymer layer, this does only lead to flux rates notsufficient for transdermal treatment. Even the addition, of loadedmolecules such as silicates or chitosan, for example, or of skinpenetration amplifiers like oleic acid or polyglycol monolaurate to thematrices containing the active ingredient salt does not lead tosatisfactory flux rates (Table 1).

Generally speaking, even an in-situ release of the base from thecorresponding salt through the addition of calcium silicate duringproduction of the adhesive matrix, as described in WO 94/07486, wouldnot lead to the flux rates through the human skin desired (Table 1). Thein-situ conversion to the free base is generally not absolute so thattoo high a proportion of the active ingredient in its protonated form ispresent in the matrix.

The compound of the general Formula 1 should therefore be added to thepolymer matrix mass, preferably already in the form of the free base atthe time of the manufacture of the inventive device. In this instanceall matrices tested led to therapeutically relevant flux rates (Table 1)TABLE 1 Loading of the active Flux μg/cm²/Day ingredient (in steadystate; after (Percent by Matrix 24 hours) weight weight Mouse HumanLot-No Contact adhesive Procedure fesoterodine) (g/m²) Skin skin20111080¹ Acrylate Solvent 15 100 705 n.d. 20302060¹ Acrylate Solvent 1587 n.d. 332.64 20111085¹ EVA Hotmelt 15 84 510 323.7 20111086¹ SiliconeHotmelt 15 63 495 n.d. 20302062¹ Silicone Hotmelt 15 100 n.d. 544.8920111087¹ SxS Hotmelt 15 89 460 383.8 20302063¹ Silicone + Hotmelt 15 83n.d. 501.09 PVAc⁶ 20002031² Acrylate Solvent 15 Fumarate 105  27 n.d.20104035^(2,3) Acrylate/OL Solvent 15 Fumarate 110  84 n.d. 20106061⁴Silicone Solvent 15 Fumarate 60 n.d. 24.2 20106043⁵ Silicone Hotmelt 15DiOH⁵ 101 n.d. 2.3n.d. = not determined;¹= fesoterodine was added to the matrix as the free base;²= Comparison example manufactured through the use offesoterodine-fumarate salt;³= Comparison example manufactured through the use offesoterodine-fumarate salt with oleic acid as the permeation enhancer;⁴= Comparison example manufactured through the in-situ release of thebase from the fumarate salt into the adhesive matrix;⁵= Comparison example manufactured through the use of the dihydroxymetabolites (2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol) fromfesoterodine;⁶PVAc = Poly Vinyl Acetate.

The salt portion of the general Formula I should therefore preferably beas low as possible. Typically the part of the compound of the generalFormula I, which is introduced into the polymer matrix in salt form,should total less than 20 percent by weight, preferably less than 10%,5% or 3% and especially preferably less than 1% of the total weight ofthe active ingredient used.

In compliance with the invention the compounds of the general Formula Iare present to over 90%, preferably to over 95%, especially preferablyto over 99% as optically, high purity enantiomers in the conformationalstructure (R). This means that less than 10%, preferably less than 3%,especially preferably less than 1% of the compounds are present in theconformational structure (S).

In an advantageous form of execution of the invention the polymer matrixhas a weight of 30-300 g/m³, contains 50-95% by weight of a polymer,preferably a self-adhesive polymer (contact adhesive) and 5-40% byweight of a compound of the general Formula I (each time based on thetotal weight of the polymer matrix).

In an especially preferred form of execution of the invention the deviceis characterized in that it

-   -   (a) exhibits a base of a maximum 50 cm²,    -   (b) incorporates a self-adhesive polymer layer, which        -   (b1) exhibits a weight of 30-300 g/m²,        -   (b2) contains 50-95% by weight of a contact adhesive,        -   (b3) contains a compound of the general Formula I in a            concentration of 5-40 percent by weight based on the total            weight of the polymer layer and especially preferred,    -   (c) the said compound of the general Formula I delivers at least        4 μg/cm²/hour with a steady-state flux rate through the human        skin over a time period of at least 24 hours.

In a further preferred form of execution of the invention the medicinecontains a compound of the general Formula I where R is selected out ofthe C₁-C₆-alkyl group, in particular methyl, ethyl, 1-propyl, isopropyl(i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl.

In a notably preferred form of execution of the invention the medicinefor transdermal delivery contains(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate(fesoterodine) in its polymer matrix as the activeingredient.

In compliance with the invention the expression “C₁₋₆-alkyl” denotes astraight chain or a branched chain hydrocarbon group with 1-6 C-atoms.

The expression “C₃₋₁₀-cycloalkyl” is understood to mean a cyclicalhydrocarbon group with 3-10 hydrocarbon atoms.

In this patent application copolymers are also subsumed under theexpression “polymer”.

In this invention a layer, stratum or paste that contains one or severalpolymers is comprehended under the expression “polymer matrix”. If thepolymer matrix is self-adhesive it is also identified as an “adhesivematrix”.

In this patent application the expression “total weight of the polymermix” is understood to mean the weight of the polymer matrix includingthe active ingredient introduced into it and possible auxiliary agents.

In the case of the inventive device it involves a customary, flat shapedtransdermal device/form of medicine of the matrix type, meaning theactive ingredient is present either embedded in a polymer layer orpolymer paste (dissolved or dispersed).

Preferably the device contains a monolithic adhesive matrix into whichthe active ingredient is embedded.

An example for a typical structure of a monolithic transdermal device isreproduced in FIG. 4. The device described there consists of theadhesive matrix, which contains the active ingredient (1), a backingwhich is inert and impermeable for the ingredients of the adhesivematrix, wherein said backing after the administration of the patch ontothe skin of the patient finds itself on the site of the patch which isremote from the skin (2) as well as a layer for protection of theadhesive matrix in storage, detachable immediately before use (3).

In compliance with the invention the surface of the transdermal devicetotals a maximum of 50 cm², preferably a maximum of 40 cm². Especiallypreferred patch sizes lie between 5 and 35 cm², notably especiallypreferred between 10 and 30 cm².

The polymer matrix, for example, the adhesive matrix, containing thecontact adhesive and the active ingredient, typically has a thickness of30-300 μm, preferably of 40-200 μm and an average weight of 30-300 g/m²,preferably from 40-200 g/m².

The active ingredient in compliance with the invention is present in thepolymer matrix, preferably in the adhesive matrix in a concentration of5-40 percent by weight, preferably 7-30 percent by weight and especiallypreferably 8-20 percent by weight based on the total weight of theadhesive matrix when the device/the medicine, for example, is intendedfor a 2-3 day application. If a medicine is to be manufactured for a7-day administration of a compound of the general Formula I then activeingredient concentrations above 15 percent by weight, preferably 20-40percent by weight are used.

The active ingredient load of the polymer layer, for example, theadhesive matrix may therefore lie between 0.15 and 12 mg/cm². Thepreferred loading strengths are loads between 0.25 and 7.5 mg/cm²,especially preferred between 0.32 and 4 mg/cm². The loading ispreferably down to a minimum of 2 mg/cm² in the case of devices for7-day applications.

In one form of execution of the invention the free base of the generalFormula I is present in a concentration that in the process leads to theover-saturation of the respective polymer matrix with the activeingredient. This may lead to the formation of the so-called microreservoirs, which are present in the matrix in the shape of drops, inparticular in a hydrophobic matrix, for example, of the silicone type.

In this situation it is preferred that the micro reservoirs containingthe active ingredient exhibit the most uniform, average sizedistribution possible of a maximum of 50% of the layer thickness of thematrix. This is able to be ensured through an intensive homogenizationof the matrix so that especially preferably an average drop in size ofup to 30 μm results.

In a different form of execution of the invention the active ingredientis present in a concentration in which it is completely dissolved in thematrix, for example, in an acrylate matrix.

In principle, the free bases of the general Formula I used for themanufacture of the devices in compliance with the invention are able tobe acquired as published in WO 99/58478. For this purpose(R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol isconverted under alkaline conditions with a suitable acid chloride, forexample, isobutyric acid chloride.

However, this reaction only leads to approximately 90%, up to a maximumof approximately 94%, of the desired main product (B). The productconsistently contains 6-10% impurities of the starting substance (A) aswell as undesired reaction products in the form of the correspondingdi-ester (C) or through the formation of the monoester (D) of the4-hydroxy group (see FIG. 1) as well as by polymerization.

However, as a general rule a purity of above 97 percent by weight ispreferred for pharmaceutical preparations.

It was found that a free base of the general Formula I could be yieldedin a purity of consistently above 97 percent by weight, preferably above98 percent by weight, especially preferably above 98.5 percent by weightand notably especially preferably above 99 percent by weight normallywith a high yield above 90 mol % if the free base is manufactured byreleasing it with an appropriate reagency from a high purity,crystalline salt.

In this application the expression “high purity” is understood to mean adegree of purity of at least 97 percent by weight, preferably above 98percent by weight, especially preferably above 98.5 percent by weightand notably especially preferably above 99 percent by weight. In thecourse of this the degree of purity is determined as described in thetechniques section.

The high purity bases of the general Formula I in compliance with theinvention can be manufactured by releasing them from the high purity,crystalline salts of the general Formula II:

where A and R have the significance given above, X⁻ is the acid residueof a physiologically compatible acid and where the C-atom marked with“*” (a star) can be present in the (R)-configuration, in the(S)-configuration or as a mixture thereof.

In the course of this the anion of the subsequently named acids comesinto consideration as an acid residue X⁻: hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, nitric acid, acetic acid,propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid,oxalic acid, succinic acid, DL-malic acid, L-(−)-malic acid, D-(+)-malicacid, DL-tartaric acid, L-(+)-tartaric acid, D-(−)-tartaric acid, citricacid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid,2-oxopropionic acid (pyruvic acid), furane-2-carboxylic acid (pyromucicacid), benzoic acid, 4-hydroxybenzoic acid, salicylic acid, vanillicacid, 4-hydroxycinnamic acid, gallic acid, hippuric acid(N-benzoyl-glycin), aceturic acid (N-acetyl glycine), phloretin acid(3-(4-Hydroxyphenyl)-propionic acid), phthalic acid, methane-sulphonicacid or orotic acid, where the acid anions hydrogen fumarate andhydrochloride are especially preferred.

The corresponding high purity bases are released from this high puritycompound of the general Formula II through the addition of theappropriate reagents.

The release reagents are, for example, alkaline compounds from the groupof

-   -   hydroxides, carbonates and alkaline-, alkaline earth- or        ammonium hydrogen carbonates    -   amines, polyamines and alkaline polyamino acids, that may also        be present both in a solution and fixed onto carriers,    -   alkaline ionic exchangers,        where weak alkaline compounds with a PK_(B) of 8-11 are        preferred.

An alkaline-, earth alkaline or ammonium hydrogen carbonate [sic] isespecially preferred as the “releasing reagent”, where sodium hydrogencarbonate is notably especially preferred.

In a preferred manufacturing process the salt of the Formula II is firstabsorbed in water and laced with a base releasing agent, for example, ahydrogen carbonate. This is then extracted by shaking using anappropriate solvent, and the organic phase evaporated to a low smallbulk until the high purity base of the Formula I remains behind as aviscous oil. Such a process is shown in more detail in Example ExecutionC.

Solvents that are suitable for such a process are in particulardichloromethane, tertiary-butyl-methyl ether, diethyl ether,ethylmethylketone as well as toluene, where dichloromethane ispreferred.

In an alternative manufacturing process the high purity salt of theFormula II is absorbed in an appropriate solvent and then conducted overa carrier, which contains ionic exchangers, for example. The eluate thencontains the high purity base of the general Formula I.

(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate hydrogen fumarate is especially preferred for use as theinitial compound of the Formula II for the production of the high purityfree base of(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate.

The production of the high purity salts of the Formula II is known fromWO 01/35957. For this purpose a solution of2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol isconverted in a base solution with an acid chloride, for example,isobutyric acid chloride. The resulting base with a low purity contentis then laced with an acid, for example, fumaric acid, while beingheated. The resulting salt of the general Formula II can then becrystallized out into appropriate solvents. The crystals are thendissolved again and re-crystallized. This process can be repeated ifnecessary until a compound of the Formula II is obtained with thedesired degree of purity. The high purity base of the Formula I isreleased from these salts as described above.

Table 2 shows the clean-up of the fesoterodine base using the processdescribed above Process Step ^(a)) Purity B or E (%) 1. Chemicalsynthesis of B from A 94.37 2. Production of the salt E from B (1) 92.583. Re-crystallization of the salt E from (2.) 99.32 4. Released highpurity base B from E (3.) 99.14^(a)) A, B, C, E: R = i-Pr, see FIG. 1

The process described allows for the first time the efficient productionof the free base of the general Formula I in high purity form and withit also for the first time the application of the high purity bases ofthe general Formula I for the production of the inventive devices forcontrolled transdermal delivery.

One preferred object of the invention is therefore a device for thetransdermal delivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration,characterized by the fact the fact that the device is manufactured by acompound of the general Formula I being introduced into a polymer layer,preferably into a self-adhesive polymer matrix (adhesive matrix) as afree base with a degree of purity of 97 percent by weight, preferablyabove 98 percent by weight, especially preferably above 98.5 percent byweight and notably especially preferably above 99 percent by weight.

One especially preferred object of the invention is a flat-shaped devicefor the transdermal delivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration,characterized by the fact the fact that the device incorporates

-   -   (a) an area of a maximum of 50 cm²,    -   (b) a self-adhesive polymer matrix, which        -   (b1) exhibits a weight of 30-300 g/m²,        -   (b2) contains 50-95% by weight of a contact adhesive,    -   (c) a compound of the general Formula I dissolved or dispersed        in the self-adhesive polymer matrix (b), which    -   (c1 ) is present in a concentration of 5-40% based on the total        weight of the polymer matrix, and is introduced to said polymer        layer        -   (c2) preferably in the form of the free base with a salt            content of less than 10 percent by weight as well as        -   (c3) preferably in a degree of purity of above 97 percent by            weight, preferably above 98 percent by weight, especially            preferably above 98.5 percent by weight and notably            especially preferably above 99 percent by weight.

In an especially preferred form of execution the compound introducedinto the polymer layer is the high purity free base from(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine).

Various polymers known in patch technology are qualified for productionof the polymer layer, where the use of contact adhesive polymers ispreferred, as outlined below and in more detail.

Generally speaking, the flux of a particular active ingredient throughthe human skin is essentially determined through the matrix used inwhich the active ingredient is embedded. Contrary to expectations inthis case all of the self-adhesive matrices used in-vitro led to highflux rates through mammalian skin (FIG. 3, Table 1). The reasons forthis are the extraordinarily good skin penetrating properties of thefree bases of the general Formula I in general and of the fesoterodinein particular.

It is assumed that on average an effective daily dose of 0.5-20 mg,normally of at least 3 mg/day, for example, 3-20 mg/day, preferably 3-15mg/day and especially preferably 4-12 mg/day of the active ingredient orof the active metabolites(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenolhas to be transported through the skin of a patient. In exceptionalcases a lower daily dose of 0.5-3 mg/day or a higher dose of above 20mg/day may be adequate or required respectively.

Table 3 shows that TTS in those cases in which the high purity-base of(R)-fesoterodine in an amount of 15 percent by weight was introducedinto appropriate adhesive matrices of the SXS or EVA type lead to fluxrates that make therapeutically desired daily doses with thecorresponding application surface of 5-50 cm² possible in the case ofthe trials using in-vitro human skin: Flux rate fesoterodine throughhuman skin (mg/day) based on the TTS size TTS size Contact adhesive 5cm² 10 cm² 20 cm² 30 cm² 40 cm² 50 cm² EVA 1.6 3.2 6.5 9.7 13 16 SXS 1.93.8 7.6 11.4 15.2 19 Silicone/Cer + 2.5 5 10 15 20 25 PVAc Acrylate 1.73.3 6.6 10 13.3 16.7 (Durotak 87-4287)

Surprisingly, in compliance with the invention, the medicine containingfesoterodine as a free base delivered transdermal, steady-state fluxrates through the human skin of above 300 μm/cm²/day in the matricestested meaning that above 13 μm/cm²/hour over a time period of at least48 hours (FIG. 2).

The in-vitro flux rates through human skin from the polymer matrices incompliance with the invention exceed those from the free solution, whichwere given in WO 00/58478, surprisingly clearly.

Through the constant high flux rates the matrices in compliance with theinvention facilitate, surprisingly though, the production of devices forthe controlled transdermal delivery of the compounds of the generalFormula I, in particular(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine free base) across the entire therapeuticallyrelevant range of doses from 0.5-20 mg/day and at steady flux rates overa minimum of 24 hours, without significantly transgressing above a totalsurface of 50 cm².

One aspect of this invention is thus a medicine for the transdermaldelivery of a compound of the general Formula I in the form of the freebase, in particular(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine free base) over a time period of at least 24hours, preferably at least 48 hours, at a steady flux rate of more than125 μg/hour, preferably 125-850 μg/hour, especially preferably 125-650μg/hour and notably especially preferably 150-500 μg/hour.

Another aspect of the invention is a medicine for the steady transdermaldelivery of a compound of the general Formula I in the form of the freebase, in particular(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine free base) over a time period of at least 24hours, preferably at least 48 hours, in a steady flux rate of more than4 μg/cm²/hour, preferably 6 μg/cm²/hour, especially preferably of morethan 8 μg/cm²/hour, 10 μg/cm²/hour or more than 12 μg/cm²/hour where theflux rates are determined according to Tanojo in a model of human skinin-vitro as specified in Example Execution 3.2.

The human skin in-vitro model used in this invention according to Tanojohas proven itself to be an excellent model in which the in-vitro fluxrates measured correlate with the in-vivo flux rates and plasma levels,which were measured in several clinical studies with various activeingredients containing aminos.

The daily flux rates measured using the inventive devices correspondwith the amount proved in clinical studies in most of the patients to bethe optimum effective dose of(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) in the case of oral administration(approximately 4-12 mg per day) and leads to therapeutic plasma levelsof 1-15 ng/ml, preferably of 2-12 ng/ml, especially preferably of 3-10ng/ml of the metabolites(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol.

Another aspect of the invention is therefore a medicine for thetransdermal delivery of a compound of the general Formula I, inparticular(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine free base) at a flux rate that leads to theproduction of a steady plasma level of 1-15 ng/ml, preferably of 2-12ng/ml, especially preferably 3-10 ng/ml of the metabolites(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenolover a time period of at least 24 hours, preferably at least 36 hours.

In this patent application the expression “steady-state” is understoodto mean a dynamic equilibrium which adjusts itself after an initial lagphase following application for the first time of the inventive device.

A “steady state flux rate” is understood to mean a flux rate thatadjusts after the initial lag phase.

In this patent application the expression “constant flux” rate isunderstood to mean a steady-state flux rate in the case of which acompound of the general Formula I is transported at an average flux ratethrough human skin, which exhibits an intra-individual variability CVover the time of a maximum of 30%, preferably a maximum of 20% or even amaximum of 10%, where CV is determined according to the equationCV=(sd:x)×100% (see the Cawello (ED) calculation in “Parameters forCompartment-free Pharmacokinetics”, Shaker Verlag, Aachen, 1999, Page112). In the course of this a daily dose is administered at an averageflux rate of daily dose: 24 (mg/hour) with a CV of 30%. To the skilledperson it is clear that a steady flux rate is only adjusted following aninitial burst effect phase (“lag phase”) after application for the firsttime of the device. The lag phase is therefore not taken intoconsideration in the calculation of the steady flux rate.

In this patent application, unless expressly stated otherwise, theexpression “flux rate through human skin” is understood to mean a fluxrate that was measured according to Tanojo in an in-vitro human skinmodel as described in Example Execution 3.2.

In this patent application the expression “constant plasma level” isunderstood to mean that the patient exhibits a defined plasma level ofthe active metabolites following an initial burst effect phase after thefirst time application of the inventive medicine above a minimum of 80%,preferably at least 85% and especially preferably at least 90% of thetime of the administration of the inventive medicine.

The devices in compliance with the invention generally contain 50-95percent by weight, preferably 70-90 percent by weight of a polymer inthe polymer layer, preferably of a pressure sensitive polymer (“contactadhesive”).

In the course of this the contact adhesives known in patch technologyare qualified in principle as a base for a self-adhesive polymer layer,such as for example, silicone adhesive, ethyl vinyl acetate (EVA-)adhesive, styrene-block-copolymer (SXS) adhesive, acrylate adhesive,polyurethane adhesive, vinyl acetate adhesive as well as adhesive gums,for example, polyisobutylene, polybutadiene, neoprene or polyisoprene aswell as appropriate mixtures of these adhesive substances.

One object of the invention is therefore a device for the transdermaldelivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration, which ischaracterized by the fact the fact that a compound of the generalFormula I preferably in the form of the free base is introduced into aself adhesive polymer layer, where the self-adhesive polymer layerincorporates at least one contact adhesive from the group of siliconeadhesive, ethyl vinyl acetate (EVA)-adhesive, styrene block copolymer(SXS)-adhesive, acrylate adhesive, polyurethane adhesive, vinyl acetateadhesive, of the adhesive gums, for-example, polyisobutylene,polybutadiene, neoprene or polyisoprene or suitable mixtures of theseadhesive substances.

In principle the manufacture of the polymer layers containing an activeingredient may take place in a solvent procedure or in a hot meltprocedure.

In a solvent procedure the active ingredient and the polymer as well asany other auxiliary agents are each dissolved in solvents and then mixedwith one another. The mixture is then spread out on foil and the solventevaporated by gentle heating.

In a hot melt procedure the polymers and any auxiliary agents arethermally melted and mixed without the use of any solvents and themeltings spread out on foil. The active ingredient is normallyintroduced directly into the liquid melt. Those polymers which aresufficiently liquid at processing temperatures from up to 200° C.,meaning that they preferably exhibit a dynamic viscosity of below 100Pa's, are particularly suitable for the hot melt procedure. The dynamicviscosity may be determined in the process as described in U.S. Pat. No.5,328,696.

The compounds of the general Formula I, in particular fesoterodine,prove themselves to be surprisingly stable at the processingtemperatures up to 200° C. in the hot melt procedure.

The known polymers of the acrylate type, the SxS type, the EVA type aswell as the silicone type are particularly suitable as contactadhesives, especially the hot-meltable silicone softener mixes. Theseadhesives exhibit a satisfactory adhesion on human skin and provideexcellent flux rates regarding the high purity bases of the generalFormula I, especially with regard to fesoterodine. These adhesives arevery compatible with the skin and suitable for pharmaceutical purposes.The properties and the manufacture of these preferred contact adhesiveswill be explained more closely in the following as examples:

Silicone Adhesives:

The preferred silicone adhesives are amine resistant, pressuresensitive, polymeric organosiloxane adhesives.

In most cases silicone contact adhesives represent polymeric dimethylsiloxanes, however in principle other organic residues, such as ethyl orphenyl groups for example, may also be available instead of the methylgroups. Amine resistant silicone contact adhesives are generallydistinguishable in that they contain no or only contain a few freesilanol functions because the Si—OH-groups were alkylated. Suchadhesives are described in EP 180 377. Condensates or mixtures ofsilicone resins and polymeric organosiloxane adhesives such as describedin US RE 35 474 are especially preferred adhesives.

Suitable adhesive substances are sold, for example, by Dow Corning asthe so-called Bio-PSA adhesive substances. In the process mixtures ofthe contact adhesive Bio PSA Q7-4301 and Q7-4201 are particularlysuitable, especially in a 40:60 to 60:40 ratio.

Patch matrices based on silicone adhesives are processed predominantlyin solvent based procedures. For this purpose a solution of contactadhesives and active ingredient are manufactured in a first step in anorganic solvent or a mixture of solvents. In a second step the solutionis spread out and laminated and the solvent is then removed. Such aprocedure is described as an example in WO 99/49852.

An alternative procedure that dispenses with the use of organic solventsis the hot melt procedure. In this procedure the polymer or the contactadhesive are melted at temperatures between 70 and 200° C., preferablybetween 90 and 160° C. and especially preferably between 100 and 150° C.and the active ingredient introduced into the homogenized matrix melt.After a brief homogenization the adhesive matrix that contains theactive ingredient is cooled again so that the active ingredient isexposed to a thermal load in general for less than 5 minutes, if desiredeven for 4, 3, 2 or even for less than 1 minute. Following this theactive ingredient is present in the solidified polymer melt. During theprocess the active ingredient is broadly shielded from criticalenvironmental influences (light, oxygen).

This procedure has the advantage over the solvent based procedure thatthe high purity bases of the general Formula I are not exposed to anysolvent influences but instead are able to be added immediately into thehot melt where after a short homogenization they are stabilized in thecooling polymer matrix. The hot melt procedure is preferably carried outin an extruder, for example in a twin screw extruder, as described in WO99/48493.

At the above mentioned processing temperatures the silicone adhesivesare too viscous, meaning they have a dynamic viscosity of above 150Pa's. Various procedures were described in the patent literature to makethe viscosity of the silicone adhesives hot-meltable through theadmixing of suitable additives (softeners). Examples of those softenersfor silicone are glycerol monolaurate or lauryl acetate as described inEP 835 136, waxes of the formula R—C(O)—OR′ as described in EP 360 467,alkylmethyl siloxane waxes as described in EP 524 775, siloxanatedpolyether waxes as described in EP 663 431 or organic waxes as describedin US RE 36,754.

Generally speaking, the softeners are added to the silicone adhesive ina quantity of 1-30 percent by weight based on the total mixture of thehot-meltable adhesive mixture. The preferred softeners are organic waxesas described in US RE 36 754, for example, ozokerite wax, ceresine wax,paraffin wax, candelilla wax, carnauba wax, beeswax or mixtures of thesewaxes, where ozokerite and ceresine are notably, especially preferred.

Ready-made hot-meltable silicone contact adhesives, in particularmixtures of silicone contact adhesives with ceresine or ozokerite may beobtained from Dow Corning, Michigan. For example, through the additionof 10 percent by weight ceresine wax to a silicone contact adhesive oftype Q7-4301, it is possible to lower the dynamic viscosity of theresulting contact adhesive mixture from above 200 Pa's to below 50 Pa'sat a processing temperature of 150° C. Such a silicone based contactadhesive mixture can be processed very well in a temperature range offrom 70° C. to 200° C. and in particular in the range between 100° C.and 150° C. in a hot melt procedure.

Surprisingly it was determined that hot-meltable silicone contactadhesives are excellently suited for the transdermal delivery of thecompounds of the general Formula I.

One object of the invention is therefore a device for the transdermaldelivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration,characterized by the fact the fact that the combination of the generalFormula I is present in a self adhesive polymer layer (adhesive matrix),where the adhesive matrix incorporates an amino resistant silicone.

The compound of the Formula I is preferably introduced into the siliconematrix in the form of the free base, especially preferably in the formof the high purity free base.

The silicone based matrix in compliance with the invention containsfesoterodine as the active ingredient.

In an especially preferred form of execution of the invention theadhesive matrix is based on a hot-meltable mixture of a silicone basedcontact adhesive and at least one softener, in particular an organicwax, for example, ozokerite.

A further aspect of the invention is a medicine for the transdermaldelivery of a compound of the general Formula I comprising an adhesivematrix that comprises:

-   -   (a) 50-99 percent by weight of a contact adhesive mixture        consisting of        -   (i) 70-99 percent by weight of an amino resistant silicone            adhesive,        -   (ii) 1-30 percent by weight, preferably 3-15 percent by            weight of an appropriate softener, preferably an organic            wax, which especially preferably is selected from the group            ozokerite wax, ceresine wax, paraffin wax, candelilla wax,            carnauba wax, beeswax or mixtures of these waxes where            ozokerite and ceresine are especially preferred,    -   (b) 1-40 percent by weight of a compound of the general Formula        I is introduced into the silicone matrix especially preferably        in the form of the free base and notably, especially preferred        in the form of the high purity free base.

One form of execution of the invention concerns a device for thetransdermal delivery of a compound of the Formula I where the compoundof the Formula I is dissolved or dispersed in a self-adhesive polymerlayer, with the proviso that in cases where the self-adhesive polymerlayer consists of silicones in which the free base fesoterodine isdispersed in the form of micro reservoirs that these silicones areeither

-   -   (a) present in a mixture with other non-silicone based polymers        or    -   (b) present in a mixture with softeners, where the mixture        exhibits a dynamic viscosity of below 100 Pa's and preferably of        less than 80 Pa's at temperatures of 200° C.

FIG. 3 shows the in-vitro flux through mouse skin which was achievedusing a silicone based patch manufactured in a hot melt procedure thatcontains ozokerite as a softener for the adhesive matrix and thatcontains the high purity free base of fesoterodine in the adhesivematrix.

EVA-Adhesives

EVA adhesives are hot-meltable contact adhesives, which are based onethylene vinyl acetate-copolymers (“EVA-contact adhesive”).EVA-adhesives such as these are described in U.S. Pat. No. 4,144,317 forexample. EVA-adhesives feature good adhesive properties, simplemanufacture and processing as well as good compatibility with skin.EVA-adhesives can be obtained, for example, from Beardow Adams (13/BA).

What was said under silicones essentially applies for the processing ofEVA-contact adhesives in a hot melt procedure, where no softeners haveto be added to the EVA-contact adhesives.

One object of the invention is therefore a device for the transdermaldelivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration,characterized by the fact the fact that the combination of the generalFormula I is present in a self adhesive polymer layer (adhesive matrix),where the adhesive matrix incorporates a contact adhesive of theEVA-type.

The compound of the Formula I is preferably introduced into theEVA-matrix in the form of the free base, especially preferred in theform of the high purity free base.

It is especially preferable the EVA-matrix contain fesoterodine as theactive ingredient.

In an especially preferred form of execution of the invention theEVA-based adhesive matrix is manufactured in a hot melt procedure.

FIGS. 2 and 3 illustrate the in-vitro flux rates through human skin andmouse skin respectively, which were achieved using an EVA-based patchmanufactured in a hot melt procedure, in the case of which the highpurity base of fesoterodine was introduced into the adhesive matrix.

SxS-Contact Adhesives

SxS contact adhesives may be processed in both solvent basedmanufacturing procedures and hot melt procedures. In this patentapplication the term “SxS contact adhesives” is understood to meanstyrene block copolymer based adhesives which support non-elastomericstyrene blocks at the ends and elastomeric blocks in the middle. Theelastomeric blocks may, for example, consist of polyethylene butylene,polyethylene propylene, polybutadiene, polyisobutylene orpolyisopropene.

Suitable SxS adhesives are described in U.S. Pat. No. 5,559,165 or U.S.Pat. No. 5,527,536 for example, and feature good adhesive properties,simple manufacture and processing as well as good compatibility withskin.

SxS contact adhesives may be obtained both commercially (e.g. as DuroTak 378-3500 at National Starch & Chemical) and manufactured for oneselfusing hot melt extrusion equipment during the production of patchescontaining active ingredient.

For instance, for this purpose appropriate amounts (of the followingcomponents at a minimum) of a styrene block copolymer (e.g. Shell KratonGX1657 or Kraton D-1107CU) are dosed into the extruder with an aliphaticand/or aromatic resin (e.g. Keyser Mackay Regalite R1090 or RegaliteR1010 or Regalite R1100) and an oil (e.g. Shell Ondina 933 or Ondina941) from the individual dosing stations, mixed there and melted. In thelast step the active ingredient is dosed into the contact adhesivemanufactured in this way in the extruder and the paste laminated on foilsheets. Typical exemplary-polymer parts by weight: polymer:resin:oilsare e.g. 100:120:20 or 100:200:50. The properties of the SxS contactadhesives can be adapted to the desired properties of the TTS (adhesivestrength, minimum cold flow, duration of adherence, releasing profile ofthe active ingredient) by varying these proportions of the amounts.

One object of the invention is therefore a device for the transdermaldelivery of a compound of the Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star is present in the (R)-configuration,characterized by the fact that the combination of the general Formula Iis present in a self adhesive polymer layer (adhesive matrix), where theadhesive matrix incorporates a contact adhesive on an SXS base.

The compound of the Formula I is preferably introduced into the SXSmatrix in the form of the free base, especially preferred in the form ofthe high purity free base.

It is especially preferred that the free base of the active ingredientbe introduced into the inventive SXS based matrix, notably especiallypreferred the high purity base of fesoterodine.

In an especially preferred form of execution of the invention theSXS-based adhesive matrix is manufactured in a hot melt procedure.

FIGS. 2 and 3 illustrate the in-vitro flux rates through human skin andmouse skin respectively, which were achieved using an SXS-based patchmanufactured in a hot melt procedure, in the case of which the highpurity base of fesoterodine was introduced into the adhesive matrix.

Due to the potential oxidative effect of the SXS adhesives, antioxidantsare preferably added to SXS-based adhesive matrices. An example for acommercially obtainable, suitable antioxidant is Irganox^(R) (CIBA).

Acrylate Adhesives:

Polyacrylates are produced through the radical polymerization of(meth)acrylic acid derivates, whereby other suitable compounds, such asvinyl acetate, for example, may be used as other monomers. It should besaid for clarification that the expression “polyacrylate” used hereincludes polymers that incorporate units which are based on acrylicacids and/or meth-acrylic acids as well as copolymers and mixtures ofthem.

As a matter of principle, in the selection of appropriate monomers theresulting contact adhesives can be constituted in such a way that theyexhibit specific properties, meaning a favorable solvent capacity forthe active ingredient, a desired flexibility of the active ingredient inthe matrix as well as a desired transfer-rate through the skin. Thetransfer rate is significantly limited by the distribution coefficientsand the resorption of the active ingredient through the skin.

The pressure sensitive contact adhesive of the polyacrylate type may bea homopolymer and/or copolymer of at least one acrylic acid and/ormeth-acrylic acid derivative in the form of a solution in an organicsolvent. The polyacrylate type contact adhesive may be cross-linkable ornon-cross-linkable. The cross-linking reagent links the polymer chainsusing reactive groups resulting in an increased cohesion of the contactadhesive.

Preferably the polymer contact adhesive of the polyacrylate typeconsists of the following monomers at a minimum:

Acrylic acid, acryl amide, hexane-acrylate, 2-ethyl-hexane-acrylate,hydroxy-ethyl-acrylate, octyl-acrylate, butyl-acrylate, ethyl-Acrylate,Glycidyl-acrylate, Methyl-Acrylate, Meth acrylic acid, Methacrylamide,Hexane-Methacrylate, 2-Ethyl-Hexane amide-Acrylate, octyl-Methacrylate,Methyl-Methacrylate, glycidyl-methacrylate, vinyl acetate, vinylpyrrolidon, allyl-acrylate.

The polymer contact adhesives of the acrylate type, cross-linkablecontact adhesives are preferred, which are polymerized from acombination of the following monomers:

2-ethyl-hexyl-acrylate/N-butyl-acrylate/butyl-acrylate/acrylic acid,2-ethyl-hexyl-acrylate/N-butyl-acrylate//vinylacetate/acrylic acid,2-ethyl-hexyl-acrylate/vinylacetate/acrylic acid,2-ethyl-hexyl-acrylate/vinylacetate/allyl-acrylate,2-ethyl-hexyl-acrylate/vinylacetate/divinyl-benzol/acrylic acid,2-ethyl-hexyl-acrylate/vinylacetate/allyl-methacrylate/acrylic acid,2-ethyl-hexyl-acrylate/vinylacetate/2-hydroxy-ethyl-acrylate,2-ethyl-hexyl-acrylate/vinylacetate/2-hydroxy-ethyl-methacrylate,2-ethyl-hexyl-acrylate/fumaric acid-diethyl-ester/acrylic acid,2-ethyl-hexyl-acrylate/maleicacid-diethyl-ester/2-hydroxy-ethyl-acryiate.

The following compounds can be named as preferred cross-linkablepreparations: Diphenyl-methane-4-diisocyanate,hexamethylene-diisocyanate, titanium-acetyl acetonate, aluminum-acetylacetonate, ferrous-acetyl acetonate, zinc-acetyl acetonate,magnesium-acetyl acetonate, zirconium-acetyl acetonate,2-ethyl-1,3-hexanediol-titanate, tetra-isooctyl-titanate,tetra-nonyl-titanate, polyfunctional propylene-imine-derivate,ether-derivate from melamine-formaldehyde-resin, high methylatedurethane-resin, imine-melamine-resin.

The non-cross linkable contact adhesives may be polymerized preferablyfrom a combination of the following monomers:

2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate,2-ethyl-hexyl-acrylate/vinylacetate,2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/allyl-acrylate,2-ethyl-hexyl-acrylate/N-N-butyl-acrylate/allyl-methacrylate,2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/divinyl-benzol,2-ethyl-hexyl-acrylate/fumaric acid-diethyl-ester/allyl-acrylate,2-ethyl-hexyl-acrylate/maleic acid-diethyl-ester/allyl-acrylate,2-ethyl-hexyl-acrylate/N-butyl-acrylate/acrylamide/vinylacetate/allyl-acrylate,2-ethyl-hexyl-acrylate/N-butyl-acrylate/iso-butyl-acrylate/vinylacetate/allyl-acrylate.

Furthermore a few contact adhesives may be used in the form of anaqueous dispersion (the dispersive type). The use of these dispersivetype contact adhesives may bring the advantage that no inflammable ortoxic solvents become vaporized during the coating and drying.

Dispersive type contact adhesives may be polymerized preferably from acombination of the following monomers:

N-butyl-acrylate/iso-butyl-acrylate/acrylic acid.2-ethyl-hexyl-acrylate/N-butyl-acrylate/acrylic acid,2-ethyl-hexyl-acrylate/N-butyl-acrylate/2-hydroxy-ethyl-acrylamide,2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/acrylamide,2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/2-hydroxy-ethyl-acrylate,2-ethyl-hexyl-acrylate/N-butyl-acrylate/allyl-acrylate/acrylic acid,2-ethyl-hexyl-acrylate/N-butyl-acrylate/vinylacetate/divinyl-benzol.

Suitable polyacrylates for use in this invention are cross-linked bymultivalent metal ions in order to improve the physical properties ofthe contact adhesive or in order to adapt it to the specificrequirements. The metal ions are normally applied in the form of metalchelate compounds which are soluble in organic solvents. Especiallysuitable cross-linking agents are aluminum acetate acetonate andtitanium acetyl acetonate.

If the contact adhesive used in compliance with this invention is apolyacrylate contact adhesive, the solubility capacity generally dependson the type and the quantity of the free functional groups in thecontact adhesive.

The most preferred contact adhesives for use in the device of thisinvention are the polyacrylates with polar groups, in particular withthe free hydroxy groups. Examples of such contact adhesives are thepolyacrylates for the manufacture of which polar monomers, such ashydroxy-ethyl-acrylate, hydroxy-ethyl-methacrylate, acrylic acid ormethacrylic acid are used, for example, in an amount of approximately1-10% (w/w), especially preferred in a quantity of 3-8% (w/w), notablyespecially preferred in an amount of 4-6% (w/w). Such contact adhesivesare obtainable commercially under the name brand Duro-Tak® (NationalStarch & Chemicals; Hamburg).

Notably, especially preferred for use in the device of this inventionare the contact adhesives of the polyacrylate type, wherehydroxy-ethyl-acrylate and/or hydroxyl-ethyl-methacrylate monomers areadmixed during polymerization in a quantity of 3-8% (w/w), notablyespecially preferred in a quantity of 4-6% (w/w).

Such a contact adhesive may be obtained according to the generalprocedure that is described in U.S. Pat. No. 5,498,418 as follows: Thecontact adhesive can be obtained through radical polymerization. In afirst step a mixture consisting of 21 to 40 percent by weight vinylacetate, 55-70 percent by weight of an acrylic acid C₂₋₈-alkyl ester and3 to 10 percent by weight of an acrylic acid C₂₋₄ hydroxyl acrylic esteris manufactured in an organic solvent with 100 percent by weightmonomers in the mixture.

In a second step a conventional cross-linked agent in an organic solventand—optionally—the active ingredient of the quality required in thetransdermal device (patch) for the intended use is admixed, if necessaryin an organic solvent.

Finally, in a third step the obtained mixture of the particular acrylatevinyl acetate copolymer is cross-linked in an additional step, conductedthrough heating and through the removal of the organic solvent or themixture of solvents used. The active ingredient obtained is “built into”the contact adhesive substance in a special way through the successiveand additional cross-linking of the special acrylate vinyl acetatecopolymer.

Alternatively the acrylate vinyl acetate copolymer can be polymerizedand cross-linked in the absence of the active ingredient. The activeingredient is then only added during the application of the acrylatevinyl acetate copolymer when the patch is manufactured. The acrylatevinyl acetate copolymer has a relative viscosity of 3.0 to 4.2 at 20° C.

Preferably the mixture contains 2-ethylhexyl acrylate and hydroxy ethylacrylate monomers in addition to vinyl acetate. Preferably thesubsequent cross-linking of the special acrylate vinyl acetatecopolymers is performed with a titanium acid ester consisting ofpolybutyl-titanate and/or titanium acetyl acetonate, preferably in aquantity of 0.3 to 3 percent by weight proportional to the weight of thecopolymer.

The following steps can cover a process for the manufacture of a TTS incompliance with this invention: As a first step the manufacture of asolution of a copolymer, in which the active ingredient, in the amountrequired for the intended use of the TTS as well as a conventionalcross-linker or a mixture of it, is optionally contained, and wherebythe copolymer is obtained through the radical polymerization of amixture of monomers consisting of 21 to 40 percent by weight vinylacetate, 55 to 70% by weight of an acrylic acid-C₂₋₈ alkyl ester and 1to 10 percent by weight of an acrylic acid-C₂₋₄ hydroxy alkylester, thecoating of the above-named solution in the layer thickness required onthe protective film of the TTS and the removal of the solvent or themixing of the solvents by heating, which results in an additionalcross-linking of the special acrylate vinyl acetate copolymer.

One form of execution of such a process is characterized by the factthat the acrylate vinyl acetate copolymer,—optionally—the activeingredient, and the cross-linkable agent are dissolved at the start in asolvent, which contains 20 to 40 percent by weight ethanol or an ethanolmethanol mixture, with a ratio of solid components consisting of 40 to60 percent by weight of the mixture of the special acrylate vinylacetate copolymer of the cross-linkable agent and the active ingredient.

In a different—preferred—form of execution of the invention the activeingredient is only added to the dispersion after cross-linking of theacrylate, which is then spread on the protective film followinghomogenization.

A particular example of execution for the preparation of such anacrylate-vinyl acetate contact adhesive is published in U.S. Pat. No.5,498,418, column 2, lines 61 to column 3, line 10. This document isquoted here as a reference.

A particularly preferred contact adhesive for use in this invention arethe commercially available contact adhesives Duro-Tak® 387-2287 andDuro-Tak® (3)87-4287 (National Starch & Chemicals; Hamburg). In anespecially preferred form of execution of the invention the Duro-Takcontact adhesive is mixed in an appropriate solvent with the desiredamount of the active ingredient and the resulting homogenous dispersionspread out in the thickness desired. Finally the solvent or the mixtureof solvents is removed at raised temperatures (50-70° C.).

One object of the invention is therefore a device for the transdermaldelivery of a compound of Formula I

in which A means hydrogen or deuterium, R stands for a group that isselected from C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl or phenyl, which may each besubstituted with C₁₋₃-alkoxy, fluorine, chlorine, bromine, iodine,nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atommarked with a star “*” is present in the (R)-configuration,characterized by the fact that the compound of the general Formula I ispresent in a polymer layer, preferably in a self adhesive polymer layer(adhesive matrix) where the polymer layer incorporates at least onepolymer of the acrylate and/or methacrylate type.

The compound of the Formula I is preferably introduced into the acrylatematrix in the form of the free base, especially preferred in the form ofthe high purity free base

It is especially preferred that the free base be introduced into theinventive acrylate-based matrix, notably especially preferred the highpurity base of fesoterodine.

FIG. 3 shows the in-vitro flux rates through mouse skin which wereachieved with an acrylate based patch manufactured in a hot meltprocedure in which the high purity free base of fesoterodine wasintroduced into the adhesive matrix.

Auxiliary Agents and Additives

The above described polymer matrices of the transdermal devicescontaining active ingredient in compliance with the invention maycontain other auxiliary agents and additives. Examples are buffers,solutizing agents, crystallation inhibitors, chemical stabilizers,antioxidants, other auxiliary agents for retarding as well as skinpenetration enhancers.

Skin penetration enhancers may be used, for example, to enlarge theamount of active ingredient that permeates through the skin or to shrinkthe application area of the device. Examples of the common penetrationenhancers are: Alcohols, in particular short chained alcohols such asethanol, fatty alcohols, e.g. lauryl alcohol, polyalcohols such asglycerins, amides, e.g. aromatic amides like N,N-diethyl-m-toluamide,amino acids, azones, oils like menthol or peppermint oil; fatty acidsand their esters like oleic acids, lauryl acids, isopropyl myristate orglycerol monolaurate; macrocycles such as, for example,cyclopentadecanon; phospholipids such as lecithin for; 2-pyrrolidones aswell as sulfoxides such as dimethyl sulfoxide for example.

On account of the good penetration properties of the compounds of thegeneral Formula I, forms of execution of the invention are preferred inwhich the addition of an enhancer is dispensed with.

A hydrophilic component such as a hydrophilic polymer for example, maybe added to the adhesive matrix as another component. These hydrophilicpolymers may serve as solubility facilitators or crystallizationinhibitors for the compounds of the general Formula I and contribute toa uniform distribution of the active ingredient in the adhesive matrix.

Appropriate hydrophilic polymers for use in the TTS in compliance withthe invention may, for example, be chosen from the group of thepolysaccharides, substituted polysaccharides, polyethylene oxide,polyvinyl acetate, polyvinyl pyrrolidone (PVP), PVP with appropriatesofteners, polyethylene glycols, polypropylene glycols, polyacrylates,copolymers from polyvinyl pyrrolidone and (poly)vinyl acetate,copolymers from ethylene and vinyl acetate as well as polyvinyl alcoholswith a suitable softener, for example, glycerin.

Preferred hydrophilic polymers are PVP, polyethylene oxide (PEQ),polyvinyl acetate (PVAc) as well as copolymers from PVP and vinylacetate.

The hydrophilic polymers may be added to the adhesive layer, forexample, in a portion of 0.5-40 percent by weight based on the totalweight of the adhesive layer. Preferably 2-25 percent by weight,especially preferably 2-15 percent by weight of 2-10 percent by weighthydrophilic polymers are added.

Those hydrophilic polymers which exhibit a dynamic melting viscosity ofa maximum 150 Pa's, preferably less than 120 Pa's and especiallypreferably below 80 Pa's, at temperatures below 170° C. are especiallysuitable for use in a hot melt procedure. A suitable softener, forexample, glycerin, is to be added beforehand if the dynamic viscosity ofthe hydrophilic polymer is too low at the desired processingtemperature.

The addition of the above named hydrophilic polymers may beadvantageous, particularly in the case of very hydrophobic adhesivematrices, for example, silicone, polyisobutylene or SXS matrices.

As already described in WO 01/35957, the free bases of the3,3-diphenylpropylamine-monoester tend towards a drop in concentration,for example, as a result of hydrolysis and interchange esterification.It was then surprisingly determined that the3,3-diphenylpropylamine-monoesters can be stabilized significantly inmatrices with hydrophilic constituent parts.

While, for example, the free base of fesoterodine is decomposed as anoil after storage for 6 months at 5° C. to around 3-4% a drop inconcentration cannot be established or can only be establishedessentially to a lesser extent when fesoterodine is incorporated inmatrices, which contain polar components.

Examples for such matrices as these that lead to the stabilization ofthe monoester of the general Formula I are matrices, for example, thatcontain polyacrylates, in particular polyacrylates with polar groups,EVA or mixtures of silicone adhesives with hydrophilic polymers, forexample, PVP, PVAc or PEO, (Table 4). TABLE 4 Stabilization offesoterodine in various matrices during storage 5° C. 25° C./60% RHStabilization Stabilization Manufacturing Matrix Factor¹ Factor¹ ProcessEVA 7-fold 4.5-fold Hot melt Silikon/Cer³ — — Hot melt Silicone + 2-fold  2-fold Solvent 2% PVP Silikon/Cer³ ⁺ 3-fold 2.5-fold Hot melt 5% PEOPolyacrylate No decomposition  13-fold Solvent detectable² PIB — —Solvent SXS — 1.1-fold Hot melt¹The stabilization factor was determined by the division of the averagemonthly drop in concentration of the fesoterodine base during storage asa raw material (oil) by the average monthly drop in concentration duringstorage in matrices;²until the end of the period of measurement after 6 months;³Cer = Ceresine

As Table 4 shows, the incorporation of fesoterodine in matricesconsisting of EVA adhesives, polyacrylate adhesives or mixtures ofsilicone adhesives with hydrophilic polymers such as PEO or PVP leads toa distinct stabilization of the fesoterodine and is truly independent ofthe manufacturing process (the hot melt or solvent procedure).

One form of execution of the invention therefore concerns devices inwhich the compounds of the general Formula I as a free base are subjectto a slower drop in concentration than is the case if the free base isstored under identical conditions, not embedded in a polymer as an oil.Preferred forms of execution are those which at 5° C. and/or at 25° C.lead to a 2-, 3-, 7- or 10-fold stabilization of the3,3-diphenylpropylamine monoester by comparison with storage as a freebase.

Especially preferred devices in compliance with the invention are thosein which the free base is present in a polymer layer, in which a drop inconcentration of a compound of the general Formula I occurs of less than3%, preferably of less than 2% or 1% in the case of 6-month storage at4° C. and of less than 10%, preferably less than 5% and especiallypreferably less than 3% or 1.5% in the case of 3-month storage at 25° C.and 60% atmospheric moisture.

Preferred matrices are those which contain 50-95 percent by weight of ancontact adhesive that is chosen from the group of the

-   -   acrylate adhesives as well as their copolymers, in particular        acrylate adhesives with polar groups, for example with free        hydroxy groups,    -   EVA-adhesives    -   Silicone adhesives which contain 2-25 percent by weight,        preferably 2-10 percent by weight of a hydrophilic polymer, in        particular chosen from PEO, PVP or PVAc,    -   SXS- or PIB adhesives which contain 2-25 percent by weight,        preferably 2-10 percent by weight of a hydrophilic polymer,    -   Mixtures of hydrophilic contact adhesives (e.g. polar        polyacrylates) with hydrophobic contact adhesives (e.g.        silicone, SXS or PIB adhesives).

Notably especially preferred contact adhesives for the manufacture ofthe matrices in compliance with the invention are polyacrylates, inparticular those with polar groups. These matrices exhibit both anexcellent releasing profile for fesoterodine and outstandingstabilization properties for 3,3-diphenyl propylamine monoesters.

Furthermore, the invention concerns use of the free bases of the FormulaI for the manufacture of controlled releasing transdermal forms ofdrugs.

One aspect of the invention is therefore the use of a compound ofFormula I

in the form of the free base in which R stands for C₁-alkyl,C₃-₁₀-cycloalkyl, substituted or non-substituted phenyl, and in whichthe C-atom marked with a star “*” is present in the (R)-configuration,for the manufacture of a medicine for transdermal delivery,characterized by the fact that the compound of the general Formula I isadded in the form of the free base to a polymer layer, preferably aself-adhesive polymer layer (adhesive matrix).

Preferably the compound of the general Formula I is present as a freebase with a degree of purity that is at least 98 percent by weight,preferably at least 99%, especially preferably 99.5% and notablypreferably that is at least 99.8%.

In a preferred form of execution the free base of the general Formula Iis used for the manufacture of a transdermal medicine which

-   -   (a) exhibits a surface of a maximum of 40 cm²,    -   (b) incorporates a self-adhesive polymer layer, which        -   (b1) exhibits a weight of 30-300 g/m²,        -   (b2) contains 50-95% by weight of a contact adhesive,        -   (b3) contains a compound of the general Formula I in a            concentration of 5-40 percent by weight based on the total            weight of the polymer layer,    -   (c) delivers said compound of the general Formula I with a        steady flux rate of at least 125 μg/hour through the human skin        over a time period of at least 24 hours.

A typical and preferred example for such a preferred medicine is aso-called monolithic patch, consisting of an adhesive matrix thatcontains an active ingredient (1), an inert and impermeable backing forthe constituents of the adhesive matrix (2) as well as a protectivelayer detachable immediately before use (3) (FIG. 4).

In compliance with the invention use of the high purity base of thecompound(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine) for the manufacture of the transdermalmedicine is especially preferred.

As is evident from FIG. 2 and Table 3, transdermal drugs can bemanufactured through the use of the free bases of the general Formula I(in this case: fesoterodine) in compliance with the invention, whichwhen loaded with 15 percent by weight active ingredient and with asurface of 20 cm², transport the compound of the general Formula Ithrough the human skin at a flux rate of 6-8 mg per day. Consequently,by means of an appropriate variation of the surface from 5-50 cm², adaily flux of active ingredient between 0.5 and 20 mg over a time periodof at least 1 or 2 days is possible in a simple way and without a changeto the recipe (Table 3).

By means of a variation in the concentration of the active ingredientand the loading of the device in compliance with the invention, afurther adaptation of the burst effect of the active ingredient and/or amonitoring of the duration of the release is also possible.

The devices and drugs respectively are especially suitable for thetreatment of incontinence, in particular of urge incontinence,hyperactivity of the detrusor, pollakisuria, nocturia or imperativeurinary urgency.

In addition, the invention concerns the manufacture of the devices fortransdermal delivery in.

Another object of the invention is a method for the prevention of and/ortreatment of incontinence, in particular urge incontinence,hyperactivity of the detrusor, pollakisuria, nocturia or imperativeurinary urgency through the administration of a compound of the generalFormula I, as described in the above, and/or through the administrationof a device in compliance with the invention, containing a compound ofthe general Formula I, on the skin of a mammal, in particular on theskin of a person, who requires the prevention against or the treatmentof the above named diseases.

EXAMPLE EXECUTIONS

1. Manufacture of the High Purity Free Base of Fesoterodine

A. Manufacture of the Fesoterodine Base (B. see FIG. 1, R=i-Pr)

Drops of a solution of 18.6 g isobutyric acid chloride in 250 mldichloromethane were added in approximately 10 minutes to a solution of59.8 g (175.1 mol)(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenolcooled to −3° C. (A, see FIG. 1) dissolved in 750 ml dichloromethanewith agitation and cooling by ice bath. A white substance precipitatedafter approximately 5 minutes. For this purpose, drops of a solution of17.7 g triethylamine in 250 ml dichloromethane were added in 5 minutesunder agitation and ice bath cooling. The batch was washed once witheach of 250 ml water, 250 ml approximate 5% aqueous NaHCO₃ solution and250 ml water. The dichloromethane extract dried over Na₂SO₄ wasevaporated to a low small bulk on a rotary evaporator to constantweight, whereby a sallow, high viscosity oil was left. Raw yield: 63.7 g(88.5% of the theory).

The purity of B in the HPLC in this example amounted to 94.1%. (Typicalrange for B: 90.5%-94.4%).

B. Manufacture of the Fumarate Salt (E. FIG. 1: R=i-Pr, X⁻=HydrogenFumarate) of Fesoterodine

A solution of 41.87 g (102 mmol)(R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid ester (B) in 90 ml 2-butanon was laced with fumaric acid(11.81 g, 102 mmol) with heating. Cyclohexane (20-30 ml) was slowlyadded with agitation until the onset of clouding after dissolving of theacid. The colorless, homogenous batch was initially left for 18 hours atroom temperature and then for several more hours at 0° C. Theprecipitated, colorless crystals were suctioned off, washed with alittle cyclohexane/2-butanon (90:10 percent by volume) and vacuum driedat 30° C.

Yield: 44.6 g (83.1% of the theory) of the hydrogen fumarate salt (E) ofthe (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid ester in the form of colorless small plates.

Melting point 98.8° C., a second crystallization from the same mixtureof solvents yielded the product with a melting point of 103° C.

[α]^(D) ²⁰=+6.0(c=1.0, ethanol); −19.3(c=1.0, acetonitrile).

¹H-NMR (CDCl₃): among other things 6.84 ppm for CH=from hydrogenfumarate anion.

¹³C-NMR (CDCl₃): among other things 135.58 ppm and 170.56 ppm forolefin- and carbonyl carbon from the hydrogen fumarate-anion.

The purity in this example at E (determined with HPLC) amounted to99.2%.

C. Manufacture of the High Purity Fesoterodine Base (B: FIG. 1, R=i-Pr)

250 g (0.474 mol) crystalline(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenyl-2-methylpropanoate-fumaricacid salt (E) was added to 1 liter water with agitation and heated to30° C. An almost clear solution was present after approximately 30minutes. 96.0 g sodium hydrogen carbonate was added with agitation inportions in approximately 10 minutes to the solution cooled to roomtemperature. 1 liter of dichloromethane was added to the almost clear,colorless solution. After some stirring time at room temperature (strongdevelopment of CO₂), the dichloromethane phase was cut off and washedsuccessively with each of 5% aqueous sodium hydrogen carbonate solutionand 0.2 liters of water. The filtered clear, colorless dichloromethanephase was evaporated on a rotary evaporator to constant weight at a bathtemperature of around 40° C., whereby in a final step a diaphragm pumpvacuum (ultimate vacuum 5 mbar) was applied. In the course of this(R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid ester (B) remained as an almost colorless viscous oil.

Yield: 180.6 g (92.6% of the theory)

[α]^(D) ²⁰=+5.9 (c=1., ethanol); −6.7(c=1., acetonitrile)

NMR (CDCl₃): 19,01, 19,95, 20,59, 21,12, 34,28, 36,89, 41,88, 42,32,43,90, 48,78, 64,68, 122,57, 125, 59, 126,16, 126,86, 127,96, 128,54,136,88, 138,82, 143,92, 147,90, 175,69 (ppm).

In this example the purity in the HPLC amounted to 99.0%. Typicalpurities lie between 98.7% and 99.5%.

¹H- und ¹³C-NMR: No resonance peaks detectable for the hydrogen fumarateanion (compare with E)

The long-term storage is preferably done in the dark under argon at −20°C.

D. Manufacture of the Hydrogen Carbonate Salt (E, FIG. 1: 1; R=i-Pr,X⁻=Hydrogen Carbonate)

fesoterodine (107.7 mg(R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyric acid ester, B) is covered with a layer distilled water andstirred at room temperature. After two days of stirring the reactionbatch remains unchanged two-phase. No organic material (B or E) could bedetected by thin layer chromatography in the aqueous phase at the top(silica gel, solvent system petroleum ether/acetone/triethylamine,70/20/10 percent by volume).

A slight flow of carbon dioxide gas is fed into the second phasereaction batch at room temperature with agitation. After two days thelower oil phase (fesoterodine) has dissolved totally and clearly in theaqueous phase.

¹³C-NMR-spectrum of the hydrogen carbonate salt of fesoterodine(δ-values):

14,11, 15,36, 15,51, 29,32, 31,09, 38,95, 43,31, 52,38, 60,45, 120,04,124,07, 124,33, 124,83, 126,12, 131,97, 136,55, 139,06, 144,60, 157,46(HCO³⁻), 175,75.

A good conformity results with the ¹³C-NMR-spectrum of the hydrogencarbonate salt of fesoterodine, manufactured through the dissolving ofthe base in 1M aqueous hydrochloric acid.

13,26, 15,32, 15,48, 29,29, 31,06, 38,95, 43,34, 52,42, 60,49, 120,10,124,18, 124,38, 124,85, 126,13, 131,97, 136,50, 139,02, 144,61, 175,94.

2. Manufacture of the TTS Matrices

2.1. Manufacture of a Silicone Based Matrix in a Hot Melt Procedure

8.5 g of a silicone-based contact adhesive mixture from the siliconeadhesive Bio-PSA 7-4300 (Dow Corning, Michigan) was heated to 150° C.with 5 percent by weight ozokerite or ceresine (obtainable from DowCorning) for around 20 minutes until a homogenous melt came into being.

1.5 g fesoterodine (high purity free base) was added and the mixturekept for a further 5 minutes at 150° C. The mixture was then homogenizedby hand and laminated onto a pre-warmed foil (120° C., gap width 250μm). 5 cm² pieces were cut out for the releasing tests.

2.2. Manufacture of an Acrylate Based Matrix in the Solvent Procedure

1.5 g high purity fesoterodine base was dissolved in dichloromethane andadded to a solution of 8.5 g DuroTak^(R) 387-2287 (in ethyl acetate).The resulting mixture was stirred until a homogeneous dispersion wasachieved. The dispersion was then spread out on foil and dried (Erichsen100 μm, 6 mm/sec, drying time: 30 minutes at 50° C.).

2.3. Manufacture of an SXS Based Matrix in a Hot Melt Procedure

100 parts SIS (Styrene Polyisobutylene Styrene, Kraton D1107CU), 150parts Regalite R 1090, 20 parts Ondina oil and 1 part Irganox were mixedand melted at 140° C. 1.5 g fesoterodine (high purity free base) wasadded to 8.5 g of each melt and the mixture kept at 140° C. for afurther 1-5 minutes. The mixture was then mechanically homogenized andlaminated on a pre-warmed sheet (120° C., 250 μm). Pieces of the sizedesired were cut out.

2.4. Manufacture of an EVA Based Matrix in a Hot Melt Procedure

8.5 g of the EVA hot melt adhesive was heated for around 20 minutes at160° C. until a homogenous melt was obtained. 1.5 g or more precisely1.65 g high purity fesoterodine base was added as well and the mixturethen homogenized by hand. The mixture was then laminated on a chill rollbrought to a specified temperature (120° C.). In each case 5 cm² was cutout (for permeation experiments).

3. Releasing Experiments

3.1. Determination of the Flow of Active Ingredient in the Mouse SkinModel

Belly and back skin in a thickness of approximately 120 to 150 μm wasused in a horizontal diffusion cell for the flux measurements throughmouse skin. Medium: phosphate buffer solution (0.066 molar) pH 6.2, 32°C.

Release of the active ingredient was determined by HPLC.

3.2. Determination of the Flow of Active Ingredient in the Human SkinModel

(a) Experimental Design

The determination of the fesoterodine flux through human skin wasessentially performed as described in H. Tanojo et al, J. Control Rel.45 (1997) 41-47, where instead of the silicone membrane a dialysismembrane was used [Diachema Dialysemembran, type 10.14, obtained fromthe company Dianorm, Munich, Germany, manufactured from neutralcellulose, exclusion size 5000 Da, thickness (dry): 25 μm; pretreatmentin accordance with manufacturer information].

Human skin in a thickness of approximately 250 μm was obtained from theabdomen. A TTS with a surface of 2.545 cm² was applied on human skin ofequal surface size, where the skin on the acceptor site lays on asilicone membrane (Diagram 1). PBS (0.066 molar) was used as theacceptor phase at pH 6.2 and a temperature of 32±0.5° C. The experimentswere performed over 72 hours with a 5 ml/hour flux, whereby samples weretaken every 3 hours. At the times that the samples are taken, thereleasing medium is replaced with fresh medium thermo stated at 32±0.5°C. and the amount of the released fesoterodine measured per HPLC.

The determination of the flux rate Q(t) was done based on the area ofthe measuring cell (0.552 cm²) in compliance with the formula:Q(t)=μg/cm²=fesoterodine concentration×volume of the acceptor/0.552 cm²

Diagram 1:

(b) Analytical Chemistry of the Release of the Active Ingredient

The measurement of the active ingredient flux through the skinpreparation is done per HPLC (tower Spherisorb 5CN 25 cm) under thefollowing conditions: 4 parts by volume acetonitrile/6 parts by volumeH₂O/0.1% parts by volume TFA, 35° C., 225 nm, 1 ml flux

4. Analytical Chemistry: Determining the Purity of the Active Ingredient

A HPLC method was used to determine the chemical purity of fesoterodine,which is based on the separation at a stationary reversed phase and usedfor the gradient elution of a solvent.

Materials (Exemplary Model):

Acetonitrile for the HPLC, methane sulfonic acid (<99%, Fluka), water(purified, HPCL quality), Waters Pump 510, column heater (Waters ColumnHeater Module, 35° C.), a sampling device (Waters Wisp 717, injectionvolume 20 μL), UV-detector (Shimatzu SPD 10A). Column (150×3.9 mm,Symmetry Shield RP8, Waters Part No. WAT 200655).

Mobile Phase:

Acetonitrile with 0.05% methane sulfonic acid (v/v, %), Component AWater with 0.05% methane sulfonic acid (v/v, %), Component B Gradientprogram: time (minutes) 0.0 with 15% component A and 85% Component B,after 15 minutes 60% A and 40% B, after 20 minutes 15% A and 85% B. Fluxrate: 1.2 ml/minute.

The concentrations of the reference solutions of A, B and C (FIG. 1/4,R=i-Pr) amounted to 10-250 μg/ml. Tailing with peak overlap occurred atthe higher concentrations.

Analysis:

The average values of all peak surfaces (triple determinations) wereadded and compared with 100% for analysis following the 100% method. Theareas of the individual peaks were based on this value (as a %).Retention times for A, B and C (minutes): 5.9, 9.0 and 12.6.

5. Analytical Chemistry: Determining the Residual Salt Content

200 MHz or 500 MHz ¹H-NMR-spectrums of the free base fesoterodine isabsorbed in CDCl₃ as the solvent, and characteristic resonance signalgroups are integrated electronically, such as:

δ=6.97 ppm (Duplett, aromatic hydrogen, H⁶, 1H),

δ=4.59 ppm (Singulett, HO—CH ₂, 2H),

δ=4.10 ppm (Triplett, H¹-Propyl, 1H).

The relation to the resonance signal of the anion, for example, Hydrogenfumarate (δ=6. 84 ppm, ═CH−, 2H) results in the proportion of residualsalt (as a molecular %).

1-30. (canceled)
 31. A device for transdermal delivery of a compound ofthe following Formula I:

wherein A is hydrogen or deuterium, R is C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl orphenyl, which may each be substituted with C₁₋₃-alkoxy, fluorine,chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto ordeuterium and where the C-atom marked with a star “*” is present in the(R)-configuration, and the compound of Formula I is present in a polymermatrix and can be released through the human skin in a dose of 0.5-20 mgper day.
 32. A device of claim 31 wherein the device is produced by aprocess comprising adding a compound of Formula I in free base form tothe polymer matrix.
 33. A device of claim 31 wherein the polymer matrixincorporates 55-90 percent by weight of a contact adhesive and isself-adhesive.
 34. A device of claim 31 wherein the polymer matrixincorporates one or more contact adhesives which are chosen fromacrylates, ethylene vinyl acetates (EVA), silicones or styrene blockcopolymers (SXS).
 35. A device of claim 31 wherein the polymer matrixcomprises up to 50-95 percent by weight of a hot-meltable mixture of asilicone based contact adhesive and at least one softener.
 36. A deviceaccording to claim 31 wherein the polymer matrix comprises up to 50-95percent by weight from (a) a hydrophilic contact adhesive and/or (b) amixture of a hydrophobic contact adhesive with 2-20 percent by weight,based on the total weight of the polymer matrix, of a hydrophilicpolymer and/or (c) a mixture of a hydrophilic with a hydrophobic contactadhesive.
 37. A device according to claim 36 whereby the hydrophilicpolymer is PEO, PVP or PVAc.
 38. A device of claim 31 wherein R ismethyl, ethyl, isopropyl, 1-propyl, 1-butyl, 2-butyl, tertiary-butyl,iso-butyl, pentyl or hexyl.
 39. A device of claim 31 wherein thecompound is(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine).
 40. A device of claim 31 wherein thecompound of the Formula I has been introduced into the polymer matrix ina degree of purity of above 97 percent by weight.
 41. A device of claim31 wherein the device: (a) exhibits a surface of a maximum 50 cm²; (b)comprises a self-adhesive polymer layer, which (b1) exhibits a weight of30-300 g/m², (b2) contains 50-95% by weight of a contact adhesive, (b3)contains a compound of Formula I in a concentration of 5-40 percent byweight based on the total weight of the polymer matrix; and (c) deliversthe compound Formula I with a steady flux rate of at least 4μg/cm^(2/)hour through the human skin over a time period of at least 24hours.
 42. A device of claim 31 wherein the device exhibits a base areaof a maximum of 40 cm, and the loading of the active ingredient of theself-adhesive polymer matrix amounts to 7-30 percent by weight.
 43. Adevice of claim 31 wherein the device can transport a compound of thegeneral Formula I in a dose of at least 3 mg per day over at least 24hours at a constant flux rate through the human skin.
 44. A device ofclaim 31 wherein the device comprises an adhesive matrix containing anactive ingredient (1), a backing being impermeable and inert for theconstituents of the adhesive matrix (2), and a protective layerdetachable immediately before use (3).
 45. A device for the transdermaldelivery of the free base of(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate over a time period of at least 24 hours at a constant fluxrate of at least 4 μg/cm²/hour.
 46. A method of treating a mammalsuffering or susceptible to incontinence, the method comprising:transdermally administering to the mammal a compound of the followingFormula I:

wherein A is hydrogen or deuterium, R is C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl orphenyl, which may each be substituted with C₁₋₃-alkoxy, fluorine,chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto ordeuterium and where the C-atom marked with a star “*” is present in the(R)-configuration, and the compound of Formula I is present in a polymermatrix.
 47. The method of claim 46 wherein the compound of Formula I isadded to the polymer matrix in the form of the free base.
 48. The methodof claim 46 wherein the polymer matrix is self-adhesive.
 49. The methodof claim 46 wherein the polymer matrix is manufactured in a hot meltprocedure.
 50. The method of claim 46 wherein the polymer matrix ismanufactured in a solvent procedure.
 51. The method of claim 46 whereinthe compound of Formula I is released in a dose of at least 3 mg per dayover at least 24 hours at a constant flux rate through human skin. 52.The method of claim 46 wherein the polymer matrix comprises a contactadhesive chosen from among polyacrylates, ethylene vinyl acetates (EVA),polyisobutylenes, silicones or styrene block copolymers (SXS).
 53. Themethod of claim 46 wherein the polymer matrix contains 50-95 percent byweight of a contact adhesive that is selected from the group of: (a)polyacrylates (b) EVA-contact adhesives, (c) silicone adhesives, (d)SXS-adhesives, (e) PIB-contact adhesives, wherein 2-20 percent by weightof a hydrophilic polymer is added to each of the hydrophobic contactadhesives (c), (d) and (e) based on the total weight of the polymermatrix.
 54. The method of claim 46 wherein the device (a) exhibits asurface of a maximum 50 cm², (b) comprises a self-adhesive polymermatrix, which (b1) exhibits a weight of 30-300 g/m², (b2) contains50-95% by weight of a contact adhesive, (b3) contains a compound ofFormula I in a concentration of 5-40 percent by weight based on thetotal weight of the polymer matrix and (c) delivers the compound ofFormula I with a steady flux rate of at least 4 μg/cm²/hour through thehuman skin over a time period of at least 24 hours.
 55. The method ofclaim 46 wherein R is methyl, ethyl, isopropyl, 1-propyl, 1-butyl,2-butyl, tertiary-butyl, iso-butyl, pentyl or hexyl.
 56. The method ofclaim 46 wherein the compound is(R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (fesoterodine).
 57. The method of claim 46 wherein themammal is suffering from or susceptible to urge incontinence.
 58. Themethod of claim 46 wherein the mammal is suffering from or susceptibleto hyperactivity of the detrusor.
 59. The method of claim 46 wherein themammal is suffering from or susceptible to abnormally frequentmicturation.
 60. The method of claim 46 wherein the mammal is sufferingfrom or susceptible to pollakisuria.
 61. The method of claim 46 whereinthe mammal is suffering from or susceptible to nocturia.
 62. The methodof claim 46 wherein the mammal is suffering from or susceptible toimperative urinary urgency.
 63. The method of claim 46 wherein themammal is a human.
 64. The method of claim 46 wherein the mammal isidentified as suffering from incontinence and the compound isadministered to the identified mammal.
 65. The method of claim 46wherein the mammal is identified as suffering from urge incontinence,hyperactivity of the detrusor, abnormally frequent micturation,pollakisuria and/or nocturia, and the compounds is administered to theidentified mammal.
 66. The method of claim 64 wherein the mammal is ahuman.
 67. The method of claim 65 wherein the mammal is a human.